Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTALGFW8)

• DOT Name: DNA helicase MCM9 (MCM9)
• Synonyms: hMCM9; EC 3.6.4.12; Mini-chromosome maintenance deficient domain-containing protein 1; Minichromosome maintenance 9
• Gene Name: MCM9
• Related Disease:
  46,XX ovarian dysgenesis-short stature syndrome
  Colorectal carcinoma
  Hepatocellular carcinoma
  Liver cancer
  Major depressive disorder
  Mismatch repair cancer syndrome
  Neoplasm
  Female hypogonadism
• UniProt ID: MCM9_HUMAN
• PDB ID: 7DPD; 7WI7; 7YOX; 8S91; 8S92; 8S94
• EC Number: 3.6.4.12
• Pfam ID: PF00493 ; PF17855 ; PF17207
• Sequence:
  MNSDQVTLVGQVFESYVSEYHKNDILLILKERDEDAHYPVVVNAMTLFETNMEIGEYFNM
  FPSEVLTIFDSALRRSALTILQSLSQPEAVSMKQNLHARISGLPVCPELVREHIPKTKDV
  GHFLSVTGTVIRTSLVKVLEFERDYMCNKCKHVFVIKADFEQYYTFCRPSSCPSLESCDS
  SKFTCLSGLSSSPTRCRDYQEIKIQEQVQRLSVGSIPRSMKVILEDDLVDSCKSGDDLTI
  YGIVMQRWKPFQQDVRCEVEIVLKANYIQVNNEQSSGIIMDEEVQKEFEDFWEYYKSDPF
  AGRNVILASLCPQVFGMYLVKLAVAMVLAGGIQRTDATGTRVRGESHLLLVGDPGTGKSQ
  FLKYAAKITPRSVLTTGIGSTSAGLTVTAVKDSGEWNLEAGALVLADAGLCCIDEFNSLK
  EHDRTSIHEAMEQQTISVAKAGLVCKLNTRTTILAATNPKGQYDPQESVSVNIALGSPLL
  SRFDLILVLLDTKNEDWDRIISSFILENKGYPSKSEKLWSMEKMKTYFCLIRNLQPTLSD
  VGNQVLLRYYQMQRQSDCRNAARTTIRLLESLIRLAEAHARLMFRDTVTLEDAITVVSVM
  ESSMQGGALLGGVNALHTSFPENPGEQYQRQCELILEKLELQSLLSEELRRLERLQNQSV
  HQSQPRVLEVETTPGSLRNGPGEESNFRTSSQQEINYSTHIFSPGGSPEGSPVLDPPPHL
  EPNRSTSRKHSAQHKNNRDDSLDWFDFMATHQSEPKNTVVVSPHPKTSGENMASKISNST
  SQGKEKSEPGQRSKVDIGLLPSPGETGVPWRADNVESNKKKRLALDSEAAVSADKPDSVL
  THHVPRNLQKLCKERAQKLCRNSTRVPAQCTVPSHPQSTPVHSPDRMLDSPKRKRPKSLA
  QVEEPAIENVKPPGSPVAKLAKFTFKQKSKLIHSFEDHSHVSPGATKIAVHSPKISQRRT
  RRDAALPVKRPGKLTSTPGNQISSQPQGETKEVSQQPPEKHGPREKVMCAPEKRIIQPEL
  ELGNETGCAHLTCEGDKKEEVSGSNKSGKVHACTLARLANFCFTPPSESKSKSPPPERKN
  RGERGPSSPPTTTAPMRVSKRKSFQLRGSTEKLIVSKESLFTLPELGDEAFDCDWDEEMR
  KKS
• Function: Component of the MCM8-MCM9 complex, a complex involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR). Required for DNA resection by the MRE11-RAD50-NBN/NBS1 (MRN) complex by recruiting the MRN complex to the repair site and by promoting the complex nuclease activity. Probably by regulating the localization of the MRN complex, indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs. Acts as a helicase in DNA mismatch repair (MMR) following DNA replication errors to unwind the mismatch containing DNA strand. In addition, recruits MLH1, a component of the MMR complex, to chromatin. The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression. Probably by regulating HR, plays a key role during gametogenesis.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XX ovarian dysgenesis-short stature syndrome	DISMX3TV	Strong	Autosomal recessive	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Liver cancer	DISDE4BI	Strong	Biomarker	[3]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Mismatch repair cancer syndrome	DISIXHJ2	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[7]

3 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of DNA helicase MCM9 (MCM9).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA helicase MCM9 (MCM9).	[9]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of DNA helicase MCM9 (MCM9).	[11]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DNA helicase MCM9 (MCM9).	[10]

References

• [1] [Characteristics of cancer epidemiology in the Kirghiz SSR]. Vopr Onkol. 1978;24(6):104-9.
• [2] Mutated MCM9 is associated with predisposition to hereditary mixed polyposis and colorectal cancer in addition to primary ovarian failure.Cancer Genet. 2015 Dec;208(12):621-4. doi: 10.1016/j.cancergen.2015.10.001. Epub 2015 Oct 22.
• [3] Minichromosome maintenance helicase paralog MCM9 is dispensible for DNA replication but functions in germ-line stem cells and tumor suppression.Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17702-7. doi: 10.1073/pnas.1113524108. Epub 2011 Oct 10.
• [4] GWAS and systems biology analysis of depressive symptoms among smokers from the COPDGene cohort.J Affect Disord. 2019 Jan 15;243:16-22. doi: 10.1016/j.jad.2018.09.003. Epub 2018 Sep 7.
• [5] MCM9 Is Required for Mammalian DNA Mismatch Repair.Mol Cell. 2015 Sep 3;59(5):831-9. doi: 10.1016/j.molcel.2015.07.010. Epub 2015 Aug 20.
• [6] Inhibiting the MCM8-9 complex selectively sensitizes cancer cells to cisplatin and olaparib.Cancer Sci. 2019 Mar;110(3):1044-1053. doi: 10.1111/cas.13941. Epub 2019 Feb 14.
• [7] MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency.J Clin Endocrinol Metab. 2017 Feb 1;102(2):576-582. doi: 10.1210/jc.2016-2565.
• [8] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [11] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.